Our goal is to understand the molecular and biochemical processes that underlie birth defects. Although individually rare, genetic syndromes and malformations have a large impact on childhood morbidity and mortality. We study both dysmorphic mouse and human malformation syndromes. Our laboratory's focus is the Smith-Lemli-Opitz syndrome (SLOS). This is a human autosomal recessive multiple congenital anomaly/mental retardation syndrome characterized by facial dysmorphology, mental retardation with a characteristic behavioral phenotype, growth retardation, and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. Biochemically patients with SLOS have an inborn error of cholesterol biosynthesis. Specifically they have a defect in the conversion of 7-dehydrocholesterol to cholesterol. We do not know why these children have such a variety of congenital malformations, and neurological problems. We cloned the gene encoding the 7-dehydrocholesterol reductase, and have subsequently identified mutations in this gene in more than thirty patients with Smith-Lemli-Opitz syndrome. Our laboratory continues to identify mutations in SLOS patients. This information is being used to establish a genotype/phenotype correlation for this disorder. We have also isolated the mouse gene encoding this enzyme, and have produced a mouse model for this disorder. We are using this mouse model to further our understanding of how the malformations seen in this syndrome develop, and to further our understanding of the neurophysiological basis of the neurological problems associated with this syndrome. This mouse model will also be used to investigate therapeutic interventions. We have also produced mice in which other genes involved in cholesterol biosynthesis have been disrupted. One of these mouse models has craniofacial and limb malformations. A clinical protocol to evaluate endocrine and neurological aspects of SLOS has made significant progress. In collaboration with a group of investigators at the Kennedy Krieger Institute in Baltimore, we continue to characterize the behavioral phenotype associated with SLOS. This behavioral phenotype includes autistic features, and the effect of dietary cholesterol therapy on this clinical problem is being studied. Characterization of adrenal function in SLOS patients demonstrated that many of our patients have compensated adrenal insufficiency. This finding will impact medical management of these patients. Work continues to develop a noninvasive, MRI-based technique to measure treatment efficacy in the central nervous system. SLOS is thought to be more common in individuals of Northern European descent, and very few patients of African descent have been described. However, in a recent study we showed that the carrier frequency of an SLOS mutation in Canadian Blacks is similar to the carrier frequency found in Caucasian populations. In order to determine if SLOS is truly rare in individuals of African descent or whether this syndrome is not being recognized in this ethnic group, we have established a new clinical protocol to determine the carrier frequency of the SLOS mutations in African Americans. Our laboratory is also studying two mouse models in which we have disrupted Lhx2 and Lhx9. Lhx2 and Lhx9 are two closely related LIM homeodomain proteins that regulate the expression of other genes during development. They appear to have individual and redundant functions during development. The Lhx2 mutant mouse has forebrain malformations, anophthalmia, and severe anemia. Lhx9 mutant mice do not develop gonads. The combined Lhx2/Lhx9 mutant mouse has a limb reduction malformation that we are characterizing at the molecular level.